Integrins, a family of transmembrane adhesion receptors are principal mediators of cell attachment, migration, differentiation, and survival.1 Structurally, integrins are heterodimeric receptors that are composed of large extracellular domains, one transmembrane helix, and small intracellular domains for each subunit.2 These receptors consist of an α- and a β-subunit, which associate non-covalently in defined combinations. To date, 18 α-subunits and 8 β-subunits have been identified, which associate selectively to form at least 24 integrins. In addition to their adhesive functions, integrins transduce messages via various signaling pathways and influence proliferation and apoptosis of tumor cells, as well as of activated endothelial cells.3, 4 Unique combination of integrins on the cell surface allows cells to recognize and then respond to a variety of extracellular ligands. Integrin αvβ3 is a prominent member of integrin family. It has been implicated in the pathophysiology of malignant tumors where it is required for tumor angiogenesis5 and is highly expressed on both endothelial cells in neovasculature and highly aggressive human carcinomas. Integrin αvβ3 mediates adhesion of tumor cells on a variety of extracellular matrix proteins, allowing these cells to migrate during invasion and extravasation.6, 7 In breast cancer, αvβ3 characterizes the metastatic phenotype, as this integrin is upregulated in invasive tumors and distant metastases.8-10 Antagonism of integrin αvβ3 is therefore expected to provide a novel approach for the treatment of metastatic and invasive cancers.11, 12 The combination of αvβ3 antagonists with conventional treatment modalities could increase the efficacy of the metastatic cancer therapy without additional toxicity. The αvβ3 receptor binds to a variety of extracellular matrix proteins, including fibrinogen, fibronectin, osteopontin, thrombospondin, and vitronectin largely through interaction with the Arg-Gly-Asp (RGD) tripeptide sequence.13, 14 Previously, a variety of peptidomimetic small molecule αvβ3 antagonists have been identified, some of which are active in disease models such as osteoporosis and skeletal metastatic breast cancer.12, 15-18 
The αvβ3 antagonists potently inhibit angiogenesis in a number of animal models, including mouse xenograft models, and metastases models. Inhibition of αvβ3 activity by mAbs and cyclic RGD peptides has been shown to induce endothelial apoptosis, and inhibit angiogenesis.19, 20 The αvβ3 antagonists can induce apoptosis not only in activated endothelial cells but also in αvβ3-positive tumor cells, resulting in a direct cytotoxic effect on tumor cells.21 Antagonism of αvβ3 activity has resulted in decreased tumor growth in breast cancer xenografts and melanoma xenografts.22, 23 Cilengitide, a cyclic RGD peptide in clinical trials for metastatic cancer,24 has been tested in an aggressive breast cancer model where it was shown that the combination of Cilengitide with radioimmunotherapy remarkably enhanced efficacy and increased apoptosis, compared with single-modality therapy with either agent, without additional toxicity.25 This suggests a real therapeutic potential of Cilengitide specifically, and αvβ3 antagonists in general, in combination anticancer therapy.
The αvβ3 receptor also plays a pivotal role in bone resorption. Various studies have indicated that αvβ3 receptor is the most abundant integrin in osteoclasts.26-29 αvβ3 antibodies, RGD peptides, and peptidomimetic antagonists were shown to inhibit bone resorption in vivo without notable adverse affects.30-34 On the basis of these studies, and results from initial clinical trials, αvβ3 antagonists show great promise for the treatment and prevention of osteoporosis.